Combined inhibition of PAK7, MAP3K7 and CK2α kinases inhibits the growth of MiaPaCa2 pancreatic cancer cell xenografts
Combined inhibition of PAK7, MAP3K7 and CK2α kinases inhibits the growth of MiaPaCa2 pancreatic cancer cell xenografts
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DOI：
10.1038/cgt.2009.22
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发表时间：
2009-09-01
影响因子：
6.4
通讯作者：
Dagorn, J-C
中科院分区：
文献类型：
--
作者：
Giroux, V.;Iovanna, J. L.;Dagorn, J-C
最近建立了一组激酶，其抑制增加体外胰腺癌细胞的凋亡。这项工作的目的是在小鼠异种移植模型中观察这些激酶的抑制是否会改变胰腺肿瘤的生长。在通过转染特异性siRNA抑制所选激酶后，在两种胰腺癌细胞系MiaPaCa 2和BxPC 3中评估细胞凋亡率、半胱天冬酶-3活性和细胞活力。对于体内实验，将MiaPaCa 2细胞注射到裸鼠的胰腺中，在那里它们形成肿瘤。通过重复腹膜内（i. p.）注射对所选激酶具有特异性的修饰的O-甲基（OMe）siRNA。21天后评估肿瘤体积。在选定的激酶中，PAK 7、MAP 3 K7和CK 2 α是那些在体外抑制增加凋亡最多的激酶。同时抑制其中两种可使细胞凋亡增加5倍。此外，抑制这些激酶对10种非胰腺细胞系几乎没有影响，表明胰腺特异性。在体内，OMe-siRNA诱导激酶表达的显著但不完全的抑制（45-75%）。然而，这种抑制导致肿瘤中半胱天冬酶-3活性的两倍增加和肿瘤体积的强烈减小（约75%）。通过OMe-siRNA对胰腺癌细胞明显特异性的三种存活激酶PAK 7、MAP 3 K7和CK 2a的体内抑制显著降低了异种移植的MiaPaCa 2细胞的生长。因此，该策略具有潜在的临床意义。Cancer Gene Therapy（2009）16，731-740; doi：10.1038/cgt.2009.22; 2009年4月10日在线发表
A panel of kinases whose inhibition increased apoptosis of pancreatic adenocarcinoma cells in vitro was recently established. The aim of this work was to observe in a mouse xenograft model whether inhibition of these kinases would alter pancreatic tumor growth. Rate of apoptosis, caspase-3 activity and cell viability were assessed in two pancreatic cancer cell lines, MiaPaCa2 and BxPC3, after inhibiting selected kinases by transfection of specific siRNAs. For in vivo experiments, MiaPaCa2 cells were injected into the pancreas of nude mice, where they formed tumors. Inhibition of kinases was obtained by repeated intraperitoneal (i.p.) injections of modified O-Methyl (OMe) siRNAs specific for the selected kinases. Tumor volumes were assessed after 21 days. Among selected kinases, PAK7, MAP3K7 and CK2 alpha were those whose inhibition increased apoptosis the most in vitro. Simultaneous inhibition of two of them increased apoptosis up to five times. Moreover, inhibiting these kinases had little effect on 10 non-pancreatic cell lines, suggesting pancreatic specificity. In vivo, OMe-siRNAs induced significant but incomplete inhibition of kinase expression (45-75%). Nevertheless, such inhibition resulted in a twofold increase in caspase-3 activity in tumors and a strong reduction in tumor volume (about 75%). In vivo inhibition by OMe-siRNAs of three survival kinases apparently specific for pancreatic cancer cells, PAK7, MAP3K7 and CK2a, decreases significantly the growth of xenografted MiaPaCa2 cells. This strategy is therefore of potential clinical interest. Cancer Gene Therapy (2009) 16, 731-740; doi:10.1038/cgt.2009.22; published online 10 April 2009